Camptothecin (CPT), originally isolated from the Chinese tree Camptotheca acuminate, possesses potent antitumor properties due to its inhibition of topoisomerase I (Hsiang et al., J Biol Chem 1985, 260, 4873; Layergne et al., Cancer Res 1999, 59, 2939; Saltz et al., Lancet 2003, 361, 2235). However, CPT exhibits several properties that severely limit its clinical application such as low aqueous solubility, (Lerchen et al., J Med Chem 2001, 44, 4186; Klein et al., J Med Chem 2003, 46, 190; Saltz et al., Id.) high levels of protein binding and rapid inactivation through lactone ring hydrolysis. The insolubility of CPT has severely restricted its clinical application and has led to the development of several water-soluble congeners, which are in various phases of clinical trials or in the clinic (Potmesil, Cancer Res 1994, 54, 1431). Camptothecin undergoes a reversible, pH-dependent ring opening reaction between the active lactone (closed E-ring) and inactive carboxylate (open E-ring) form, which has also been shown to be toxic: Lactone hydrolysis is also enhanced by the specific binding and sequestration of the carboxylate form to various proteins, such as human serum albumin, in the biological matrix, which shifts the equilibrium further toward the carboxylate form. Thus, the clinical utility of CPT has been severely hindered by the hydrolytic instability of its E-lactone ring in blood serum. Additionally, considerable variability in the oral and intravenous bioavailability of CPT suggests poor cellular and tumor uptake of unmodified CPT drugs (Sinka et al., J Control Release 2004, 100, 275).
Structure of Camptothecin (CPT) in Lactone (1) and Carboxylate (2) Forms
The issues, above, are not limited to camptothecin but are also shared to certain extent by many of the pharmacologically active derivatives of camptothecin. Accordingly, what are needed are new compositions of new analogs of camptothecin and camptothecin derivatives that allow greater stability and delivery of active drugs, while maintaining high loading and concentrations of the drug in the composition.